SW033291 Attenuates AKI by Inhibiting Ferroptosis: Mechanistic Insights (as Radical-Trapping Antioxidants)

Background: Acute kidney injury (AKI) is a prevalent and severe clinical syndrome characterized by a high incidence, significant mortality, and poor prognosis. AKI not only significantly increases the risk of in-hospital mortality but is also closely associated with the development of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Currently, interventions for AKI primarily rely on supportive care and renal replacement therapy, with a lack of effective pharmacological treatments, highlighting the urgent need to identify novel therapeutic targets and intervention strategies. SW033291—a novel inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH)—has attracted attention. Previous studies have mainly focused on the effects of SW033291-mediated prostaglandin signaling in tissue regeneration. Recently, we have discovered that SW033291 can act as a Radical-Trapping Antioxidants (RTA) to directly eliminate lipid peroxides and thereby inhibit ferroptosis. This suggests that SW033291 may function in tissue regeneration and cell death respectively in vivo by regulating the prostaglandin signaling pathway and as a RTA to inhibit ferroptosis. However, its specific contribution and underlying mechanisms in AKI remain largely unexplored. Methods: In vitro, mouse tubular epithelial cells and primary renal tubule tissues were cultured and treated with SW033291, followed by induction of ferroptosis. Cell viability, lipid peroxidation, and ferroptosis-specific markers were assessed. In vivo, mouse models of ischemia-reperfusion injury AKI (IRI-AKI) was utilized. Mice were administered SW033291, and renal function, histopathology, and ferroptosis-related biomarkers were evaluated. Mechanistic studies included quantification of lipid peroxidation and anti-ferroptosis effect using chemically modified SW033291 analogs. Results: 1. SW033291 demonstrated potent anti-ferroptosis effects in both primary isolated renal tubular cells and HK-2 cells, independent of 15-PGDH inhibition. 2. In mouse models of IRI-AKI, SW033291 provided significant tissue protection primarily by inhibiting ferroptosis. 3.Mechanistically, SW033291 specifically inhibited ferroptosis by directly scavenging lipid peroxides. Conclusion: SW033291 effectively protects against ferroptosis in renal tubular cells and ameliorates acute kidney injury in vivo by scavenging lipid peroxides. Funding: Government Support – Non-U.S.